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Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy
- Source :
- Cell Death and Differentiation
- Publication Year :
- 2012
-
Abstract
- Cancer stem cell (SC) chemoresistance may be responsible for the poor clinical outcome of non-small-cell lung cancer (NSCLC) patients. In order to identify the molecular events that contribute to NSCLC chemoresistance, we investigated the DNA damage response in SCs derived from NSCLC patients. We found that after exposure to chemotherapeutic drugs NSCLC-SCs undergo cell cycle arrest, thus allowing DNA damage repair and subsequent cell survival. Activation of the DNA damage checkpoint protein kinase (Chk) 1 was the earliest and most significant event detected in NSCLC-SCs treated with chemotherapy, independently of their p53 status. In contrast, a weak Chk1 activation was found in differentiated NSCLC cells, corresponding to an increased sensitivity to chemotherapeutic drugs as compared with their undifferentiated counterparts. The use of Chk1 inhibitors in combination with chemotherapy dramatically reduced NSCLC-SC survival in vitro by inducing premature cell cycle progression and mitotic catastrophe. Consistently, the co-administration of the Chk1 inhibitor AZD7762 and chemotherapy abrogated tumor growth in vivo, whereas chemotherapy alone was scarcely effective. Such increased efficacy in the combined use of Chk1 inhibitors and chemotherapy was associated with a significant reduction of NSCLC-SCs in mouse xenografts. Taken together, these observations support the clinical evaluation of Chk1 inhibitors in combination with chemotherapy for a more effective treatment of NSCLC.
- Subjects :
- medicine.medical_treatment
Fluorescent Antibody Technique
Mice, SCID
Deoxycytidine
Mice
Mice, Inbred NOD
Carcinoma, Non-Small-Cell Lung
Tumor Cells, Cultured
Enzyme Inhibitors
Non-Small-Cell Lung
Mitotic catastrophe
Cultured
Blotting
Cell Cycle
chemoresistance
Cell Differentiation
Cell cycle
Chk1 inhibitors
Tumor Cells
Neoplastic Stem Cells
Female
lung cancer stem cells
Western
medicine.drug
Cell Survival
Blotting, Western
Biology
SCID
Cancer stem cell
Settore MED/04 - PATOLOGIA GENERALE
medicine
Animals
Humans
CHEK1
Lung cancer
mitotic catastrophe
Molecular Biology
Cell Proliferation
Cisplatin
Chemotherapy
Original Paper
DNA damage
Checkpoint Kinase 1
DNA Damage
Protein Kinases
Xenograft Model Antitumor Assays
Cell Biology
Carcinoma
Cancer
medicine.disease
Gemcitabine
respiratory tract diseases
chk1 inhibitors
dna damage
Immunology
Cancer research
Inbred NOD
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Cell Death and Differentiation
- Accession number :
- edsair.doi.dedup.....fee377cee64831635aa5ddd4a17c113c